The present invention generally relates to the field of cell culture; and more particularly to an automated system for management of culturing cells and manipulating the cultured cells.
Basic operations for culturing cells may include, but are not limited to, initiation of a cell culture, maintenance of cell culture (e.g., storage under appropriate environmental conditions, replacement with tissue culture medium to renew nutrient availability, when desired in promoting cell growth), harvesting (e.g., harvesting the cultured cells and/or cell culture medium, particularly when the culture medium contains a substance produced by the cultured cells), and termination of the cell culture. A cell culture may be manipulated by one or more means that may include, but is not limited to: changing the environmental conditions to which the cell culture is exposed; treating the cultured cells with a biological substance for either evaluating the effect of the substance on the cultured cells, or for inducing the cultured cells to respond in a morphological, physiological, biological, or biochemical manner; and evaluating cultured cells by detecting and/or measuring (xe2x80x9cdeterminingxe2x80x9d) one or more cell culture parameters which comprises one or more parameters of cultured cells and/or one or more parameters of the cell culture medium. As known to those skilled in the art, a parameter of cultured cells may include, but is not limited to, growth rate, morphology (e.g., size, shape, and the like), state of differentiation, granularity, migration, light scatter, attachment (anchorage-dependency or lack thereof), and the like. A parameter of the cell culture medium may comprise a chemical, biological, or physical characteristic of the medium (including, but not limited to, pH, oxygen content, CO2 content, nutrient content (e.g., glucose), and the like); or the presence of a product of cultured cells which is secreted, excreted, or released into the cell culture medium (including, but not limited to, metabolite, cytokine, recombinant product (e.g., protein, peptide, and the like), and the like). In culturing and manipulating cells, performed is a sequence of dissociated operations, wherein the sequence may be varied depending on the desired objective.
Genomics, proteomics, and drug discovery are generating a need for expanded versatility of applications for manipulating cell cultures, as well as a greater need for efficient and economical growth of cultured cells in high volume (xe2x80x9chigh-throughput cell culturexe2x80x9d). For example, in developing and testing one or more biological substances (e.g., including, but not limited to, genetic vectors, genetic sequences, vaccines, drugs, growth factors, cytokines, chemicals, enzymes, or the like), it may often be desirable to evaluate the response of cultured cells after treatment with a biological substance; and additionally to evaluate the responses in a multitude of treated cell cultures being grown simultaneously. It is known in the art (see, e.g., Genetic Engineering News 20:26, Sep. 1, 2000) that while a large cell culture lab may be able to handle simultaneously a few dozen cell cultures, the present systems are not adequate to meet industry""s current demands for high-throughput cell culture. Despite advances in bioautomation technology, a bottleneck in implementing high-throughput cell culture is a lack of automated systems which maximize the number of cell cultures that can be grown and manipulated simultaneously. Thus, not only is there a need for an automated system for carrying out basic operations for culturing cells, there is also a need for an automated system for manipulating cultured cells (e.g., treating cultured cells with one or more biological substances, and may further include evaluating cultured cells for one or more cell culture parameters). Such an automated system would be capable of, as an integrated unit, performing dissociated operations associated with culturing cells and with manipulating cultured cells.
Conventional cell culture devices and manual methods for culture are not adequate for high-throughput cell culture. In a manual method of culturing cells, a cell culture device containing cultured cells is removed from a controlled environment (e.g., that maintains a specific atmosphere, temperature, and humidity) provided by a conventional tissue culture incubator. Thus, once removed from this controlled environment, the cultured cells may be subject to a rapid change in the environment. Currently, to perform one or more operations of cell culturing (e.g., removal of cell culture medium, addition of fresh tissue culture medium, removal of cultured cells, addition of cells to be cultured, and the like), it is first necessary to open the cell culture device to allow for pipetting. In that regard, conventional cell culture devices, such as flasks and roller bottles, have screw caps which require temporary removal to allow for pipetting of one or more of tissue culture medium, cell culture medium, or cells into or out of the cell culture device. Thus, opening and closing a number of cell culture devices during routine culturing is highly labor intensive, and necessitates an open system, at least part of the time, which greatly increases a breach in the maintenance of sterility of the cultures. Further, in a harvesting operation which requires separation of substantially all of the cell culture medium from the cultured cells (e.g., in harvesting the cell culture medium and/or the cells), transfer of the cell culture to and from a vessel for centrifugation is required. This xe2x80x9charvestingxe2x80x9d operation represents additional time in which the cells are removed from a controlled environment, and represents an additional risk in breaching the maintenance of sterility of the culture. Additionally, due to the relative inefficient gas transfer through the screw cap, a large volume of air space (relative to the growth surface) is required in conventional cell culture devices; and hence, their overall size is rather bulky. Therefore, a tissue culture incubator can accommodate only a relatively limited number of conventional cell culture devices simultaneously, in adding to the difficulty and expense of high-throughput cell culture.
Thus, there is a need for an automated system for performing basic operations for culturing cells, and which may be used for high-throughput cell culture.
The present invention provides an automated system for management of cell cultures (xe2x80x9can automated cell management systemxe2x80x9d). The terms xe2x80x9ccell managementxe2x80x9d and xe2x80x9cmanagement of cell culturesxe2x80x9d are used synonymously to mean that the automated system of the present invention can perform operations for culturing cells, and operations for manipulating cell cultures, as will be more apparent from the following descriptions. Thus, provided is an automated system for culturing cells, and manipulating cell cultures.
It is a primary object of the invention to provide an automated system that may be used for high-throughput cell culture.
It is another object of the present invention to provide an automated cell management system capable of integrating into one unit the capability to perform dissociated operations of cell culturing and cell culture manipulation.
It is another object of the present invention to provide an automated cell management system that can be programmed to perform and control various operations of cell culturing and cell culture manipulation.
Briefly, the automated cell management system according to the present invention comprises an apparatus comprising: a mechanism for incubating cells comprising an housing having a chamber used to provide controlled environmental conditions in which cells may be cultured and manipulated (such chamber may also be referred to as a xe2x80x9cbiochamberxe2x80x9d); a storage array (rack system) for accommodating a plurality of cell culture devices, wherein a cell culture device comprises a housing (preferably a frame) to which is secured (by a leak-proof sealing) at least one gas permeable, liquid impermeable membrane in forming one or more chambers for culturing cells (e.g., a cell culture device comprises one or more chambers for culturing cells, and at least one gas permeable, liquid impermeable membrane forms at least one surface (wall) of the chamber to permit transfer of gases in and out of the chamber, and wherein an opposing wall may comprise a second membrane or a rigid plastic surface or a combination thereof); a loading station for introducing cell culture devices into the biochamber, and more preferably, for introducing cell culture devices into the storage array contained within the biochamber; a handling device which comprises a mechanism for moving one or more cell culture devices within the biochamber (e.g., to a specific desired position in the interior of the biochamber); a means for harvesting a cell culture component from a cell culture device, wherein the cell culture component comprises cultured cells, cell culture medium, or a combination thereof; and one or more processing stations. A processing station is capable of performing a process selected from the group consisting of aspirating a substance from a cell culture device, injecting a substance into the cell culture device, or a combination thereof (e.g., can perform both operations of aspirating and injecting); wherein, preferably, a substance comprises tissue culture medium, cell culture medium, cells, one or more biological substances, one or more reagents, or a combination thereof. The automated cell management system may further comprise one or more components selected from the group consisting of: a centrifuge for centrifuging one or more cell culture devices; a mechanism for tracking (e.g., one or more of locating or identifying or cataloging) a cell culture device in relation to (e.g., for loading into, or within the biochamber of, or discharged from, or a combination thereof) the automated cell management system; a plurality of reservoirs which are in fluid communication with a station selected from the group consisting of one or more processing stations, one or more evaluation stations, and a combination thereof; a discharge station for permitting removal of cell culture devices from the automated cell management system, and more preferably, into which is delivered cell culture devices unloaded from the storage array for subsequent removal from the automated cell management system; a microprocessor for controlling functions and programmable operations of the automated cell management system, and which may further process and store data generated by the functions and programmable operations of the automated cell management system; one or more evaluation stations for measuring one or more cell culture parameters; one or more means for sterilization of components and surfaces within the biochamber; or a combination thereof.
These and other objects and advantages of the invention will become more apparent from the following detailed description taken in conjunction with the accompanying drawings.